Nuclear receptors regulate diverse aspects of eukaryotic development and homeostasis. In addition to being ligand-dependent transcriptional regulators nuclear receptors are also involved in extranuclear functions including intracellular kinase signaling and crosstalk. These actions are often controlled by hormone binding, coregulator binding as well as post-translational modifications. Recently small molecules have been identified that can bind to several different regulatory sites on the surfaces of nuclear receptors. These compounds and new ligand conjugates of the androgen receptor (AR) and thyroid hormone receptor (TR) provide an ideal platform to explore new methods to regulate protein function with hormone receptor targeting small molecule conjugates. These will be addressed through three specific aims. Aim 1. Thioester based conjugates will be developed as NHR targeting histone/protein acetyl transferase mimics (HPAT mimics). Three ligand scaffolds, including a new AR targeting scaffold developed by this lab, will be used to direct acylations to different surfaces of the AR known to regulate AR function. We will explore in vitro efficacy and specificity of ligand-directed acyl transfer reactions. Additionally we will explore new peptide based NHR targeting HPAT mimics. Aim 2. We will develop and evaluate novel PAMAM dendrimer-NHR ligand conjugates which can i. selectively target AR expressing cells ii. selectively target extranuclear AR, iii. block nuclear localization of AR, iv. catalytically affect AR turnover/downregulation. Aim 3. We have previously developed a novel class of antiandrogens that shows a unique ability to evade formation of resistant clonal populations in LNCaP (prostate cancer) cells in vitro. We will explore the lilgand-dependent mechanisms which allow androgen dependent cells to acquire resistance under selection. Taken together, these aims, which primarily focus on the AR, explore new chemical approaches to the regulation of nuclear receptor function that in principle can be applied to other members of the nuclear receptor family.